IE58497B1 - New process for the preparation of derivatives of 4h-1, 2,4-triazole, the new triazoles so obtained, their use as medicaments and the pharmaceutical compositions containing them - Google Patents

Abstract

1. Process for the preparation of compounds of formula (IA ) : see diagramm : EP0176444,P12,F1 in which R1 , R2 , R3 and R4 identical or different, in whatever position on the benzene nuclei, represent a hydrogen atom, an hydroxyl radical, an alkyl radical containing from 1 to 4 carbon atoms, an Oalk1, radical, alk1 representing an alkyl radical containing from 1 to 4 carbon atoms, an NH2 , NHalk2 radical, alk2 representing an alkyl radical containing from 1 to 4 carbon atoms ; a radical see diagramm : EP0176444,P12,F2 alk3 and alk'3 , identical or different, representing an alkyl radical containing from 1 to 4 carbon atoms, a halogen atom, a CF3 radical or an NO2 radical, or R1 and R2 and/or R3 and R4 together form a methylenedioxy radical, RA represents a -CHOH-alk4 radical, or a see diagramm : EP0176444,P12,F3 radical, alk4 and alk5 , identical or different, representing an alkyl radical containing from 1 to 4 carbon atoms, in their racemic or optically active forms, as well as their addition salts with acids characterized in that a compound of formula (II) : see diagramm : EP0176444,P13,F3 in which R1 , R2 , R3 and R4 have the significances already indicated, is submitted to the action of a chlorination agent so as to obtain an imidyl chloride of formula (III) : see diagramm : EP0176444,P13,F4 which is submitted to the action of a hydrazide of formula (IV) see diagramm : EP0176444,P13,F5 in racemic or optically active form, in which Z is a see diagramm : EP0176444,P13,F6 group, alk4 being an alkyl radical containing from 1 to 4 carbon atoms, so as to obtain a compound of formula (V), in racemic or optically active form : see diagramm : EP0176444,P13,F7 which is cyclized by heating so as to obtain a compound of formula (I), in racemic or optionally active form, in which R is a see diagramm : EP0176444,P13,F8 group, which if desired is esterified so as to obtain a product of formula (I) in which RA is a see diagramm : EP0176444,P13,F9 group, which products of formula (I) are submitted, if desired, to the cation of an acid so as to form a salt.

Description

The present invention is concerned with a new process for the preparation of derivatives of 4 H - 1,2,4 - triazole, the new triazoles so obtained, their use as medicaments and the pharmaceutical compositions containing them.

The subject of the present invention is a process for the preparation of compounds of formula (IA): in which Rg, Rg, Rg and R^, identical or different, in whatever position on the benzene nuclei, represent a hydrogen atom, an hydroxyl radical, an alkyl radical containing from 1 to 4 carbon atoms, an Oalkg radical, alk^ representing an alkyl radical containing from 1 to 4 carbon atoms, an NHg, NHalkg radical, alkg representing an alkyl radical containing from 1 to 4 carbon atoms; a radical — N alkg and alk’^, identical or different, representing an alkyl radical containing from 1 to 4 carbon atoms, a halogen atom, a CFg radical or an NOg radical, or Rg and Rg and/or Rg and R^ together form a methylenedioxy radical, R^ represents a -CHOH-alk^ radical, or a -CH-alk4 O-CO-alk, - 2 radical, alk^ and alk^, identical or different, representing an alkyl radical containing from 1 to 4 carbon atoms, in their racemic or optically active forms, as well as their addition salts with acids characterized in that a compound of formula (II): in which Rp Rp Rg and R^ have the significances already indicated, is submitted to the action of a chlorination agent so as to obtain an imidyl chloride of formula (III): which is submitted to the action of a hydrazide of formula (IV) h2n-nh-co-z in racemic or optically active form, in which Z is a -CH-alk4 OH group, alk^ being an alkyl radical containing from 1 to 4 carbon atoms, so as to obtain a compound of formula (V), in racemic or optically active form: - 3 which is cyclized by heating so as to obtain a compound of formula (I), in racemic or optically active form, in which R is a -CH-alk OH group, which if desired is esterified so as to obtain a product of formula (I) in which is a -CH-alk4 0-C0-alk5 group, which products of formula (I) are submitted, if desired, to the When Rη » Rj’ ^3 and R4 represent an alkyl radical, it is preferred to be a methyl, ethyl, n-propyl, isopropyl or n-butyl radical.

Alk1, alk2, alk^, alk’^, alk^ and alkg preferably represent a methyl, ethyl, n-propyl, isopropyl or an n-butyl radical.

When Rp R2> R^ and R^ represent a halogen atom, it would be a fluorine, chlorine, bromine or iodine atom, and preferably a chlorine or bromine atom, The present invention has more particularly as its subject the preparation process described above, characterized in that at the start, a compound with the formula (II) is used in which one of the two substituents R^ or represents a hydrogen atom and the other substituent represents either a methoxy group in para, or a NO^ group or a dimethylamino group in para and in which one of the two substituents R^ or Rjj represents a hydrogen atom and the other substituent represents either a methoxy group in para, or a NO^ group or a dimethylamino group in para and a hydrazide with the formula (IV) in which Z represents either an ethyl radical, or a radical -CHOH-alk^, alkjj representing an alkyl radical containing from 1 to 4 carbon atoms, in the racemic or optically active form, and in that in the case where R^ or and/or R^ or R^ represent a group N02 in para, the corresponding compounds are converted into compounds in which R1 or and/or R^ or R^ represent a dimethylamino group in para.

Naturally, the terms racemic or optically active can only designate compounds which include at least one asymmetric carbon.

The present invention is concerned also with compounds with the formula (IA) : (IA) in which , R2, R^ and R^, being identical or different, in any position on the benzene nuclei, represent a hydrogen atom, a hydroxyl radical, an alkyl radical containing from 1 to 4 carbon atoms, a radical Calk^, alk1 representing an alkyl radical containing from 1 to 4 carbon atoms, a radical NH2 or NHalk2, alk2 representing an aikyl radical containing from 1 to 4 carbon atoms, a radical· -N alk^ and alk'^, being identical or different, representing an alkyl radical containing from 1 to 4 carbon atoms, a halogen atom, a radical CF^ or a radical N02, or R^ and R2 and/or R^ and R^ together form a methylene dioxy radical and in which R represents a radical -CHOH-alk.,, alk^ representing an alkyl radical containing from 1 to 4 carbon atoms or a radical -CH-alk^ , alk^ and alk^ being identical or different, AcO-alk representing an alkyl radical containing from 1 to 4 carbon atoms, in their racemic or optically active forms, as well as their salts of addition with acids.

Among the salts of addition with acids, there can be cited those formed with mineral acids such as hydrochloric, hydrobromic, sulphuric or phosphoric acids, or with organic acids such as acetic, propionic, maleic or hemi-succinic acids.

The invention is concerned particularly with the compounds with the formula (IA) for which one of the two substituents R1 or R2 represents a hydrogen atom, and the other substituent represents either a methoxy group in para, or a dimethylamino group in para, and for which one of the two substituents R^ or R^ represents a hydrogen atom and the other substitutent represents either a methoxy group in para, or a dimethylamino group in para, in their racemic or optically active forms, as well as their salts of addition with acids, and quite particularly 5-C4-(dimethylamino)phenyl]~4-(4-methoxyphenyl) a -methyl 4H-1,2,4triazole-3-methanol in racemic or optically active form, and its salts of addition with acids.

The products with the formula (I) , with the exception of the products with the formula (IA), have already been claimed in the Belgian patent No. 890,035.

In this patent, the products with the formula (I) are prepared 5 particularly by the following process : - the compound with the formula (III’) III' is submitted to the action with the formula : of hydrazine in order to obtain a compound N_MHa II which is submitted to the action of an acid or of a functional derivative of an acid XCO^H in which X represents particularly an alkyl radical containing from 1 to 4 carbon atoms, in order to obtain the compound with the formula (V) : which is cyclized by heating, so as to obtain the compound with the formula (I), in which R^ R^, R^ and are defined as previously and R represents an alkyl radical containing from 1 to 4 carbon atoms.

In the process previously described, the intermediate amidrazone 20 (IV) obtained is unstable, and impurities, in particular, tetrazines, form during the synthesis. The formation of these degradation products makes the purification of the amidrazone and of the acylamidrazone (V) formed thereafter difficult.

In the new process of the invention, there is no unstable intermediate, the acylamidrazone (V) is easily obtained ; it is stable, devoid of impurities, and thus easily purifiable.

In a preferred method of carrying out the invention process : - The chlorated reagent enabling the imidoyl chloride (III) to be obtained is advantageously thionyl chloride or phosgene. The phosphorus pentachloride or the phosphorus oxychloride can also be utilized.

- Tne reaction enabling imidoyl chloride (III) to be obtained can be carried out, without a solvent, simply at reflux of the chloriding reagent used.

If the reaction is carried out in the presence of a solvent, the latter is, for example, toluene, benzene or dichloromethane.

- In the case where R^, R2 , or represent a sensitive function, such as, for example, the function -N /alk3 the chloriding alk' reagent is preferably phosgene and the reaction is carried out at low temperature, preferably between -3θ° C and -60° C. Furthermore, in this particular case, the reaction can be carried out in the presence of a tertiary base, such as pyridine or triethylamine which enables the hydrochloric acid formed to be eliminated.

- The condensation between the imidoyl chloride (III) and the hydrazide (IV) is carried out in a solvent such as toluene or benzene, and the reaction can also be carried out at reflux of this solvent.

The esterification reaction in order to obtain a product with the formula (I) in which R = -CH-alk„ is carried out in the usual I 4 O-CO-alk^ conditions.

Naturally, once a compound with the formula (I) is prepared, there can be applied variations evident to a chemist to the substituents Rp R2, Rg and R^. For example, a hydroxyl can be etherified or esterified, an 0-alkyl group can be cleaved to obtain a hydroxyl group, a N02 group can be converted into a NH2 group or into a N (alkyl )„ group, or a fluorated derivative can be substituted by an amine.

The compounds with the formula as defined above, as well as - 8 their salts of addition with acids offer useful pharmacological properties. They offer, in particular, a very good analgesic activity. Furthermore, the 5-[4C(dimethylamino)phenyl]-4-(methoxyphenyl) These properties justify their use in therapeutics, and the invention also has as its subject as medicaments the products as defined by formula I above, as well as the salts of addition with pharmaceutically acceptable acids of the said products with the formula I..

A The present invention is concerned in particular, as medicaments, with the compounds with the formula I for which one of the two substituents R^ or R^ represents a hydrogen atom, and the other substituent represents either a methoxy group in para, or a dimethylamino group in para and for which one of the two substituents or R,. represents a hydrogen atom, and the other substituent represents either a methoxy group in para, or a dimethylamino group in para, in their racemic or optically active forms, as well as their salts of addition with pharmaceutically acceptable acids.

The present invention has quite particularly as its subject, as medicaments, 5-C4-(dimethylamino)phenyl-4-(4-methoxyphenyl)-qi-methyl-4H-1,2,4-triazole-3-methanol and its salts of addition with pharmaceutically acceptable acids. ( The medicaments which are the subject of the invention can be used in the treatment of muscular, articular or nervous pains, of rheumatic affections, of dental pains, of shingles and migraines, and also as a complementary treatment in infectious and febrile states.

-C4-(dimethylamino) phenyl]-4-(4-methoxyphenyl)-«-methyl-4H-1 ,2,4-triazole-3-methanol can itself be recommended for the treatment of degenerative inflammatory diseases such as osteoarthrosis, various collagenoses (tendinitis, etc...), rheumatismal diseases, rheumatic polyarthritis, enkylosing spondylarthritis, as well as in the treatment of other diseases of auto-immune nature such as disseminated erythrematou3 lupus, glomerulonephritis, multiple sclerosis.

The invention is extended to the pharmaceutical compositions containing the medicaments defined above as active principle.

These pharmaceutical compositions can be administered by oral or rectal route, by parenteral route or by local route as topical application on the 3kin and the mucosa.

These compositions can be solid or liquid and can be presented in 5 the pharmaceutical forms currently utilized in human medicine, such, for example, as plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels and preparations in aerosols; they are prepared according to the usual methods. The active principle can be incorporated with the excipients 1C usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin paraffin derivatives, glycols, the various wetting, dispersing or emulsifying agents and preservatives.

The posology varies in particular as a function of the administration route, the affection treated and the subject concerned.

For example, for an adult, it can vary between 20 mg and 2 g of active principle per day by oral route.

The compounds with the formula (II) used as starting products for the invention process are prepared as indicated in the Belgian patent No. 890 035. (In this patent, the products with the formula (II) are not isolated, because they react directly with the phosphorus pentasulphide to give the products with the formula (III’)).

The compounds with the formula (IV) are prepared in a standard way by making a product with the formula : Jr C-H^OC-R, R having the significance 11 II 0 CH.O-C-R 3 ti given for the products with the formula (I), react on hydrazine hydrate The compounds with che formula (III) are new chemical products, with the exception of N-(4-methoxyphenyl)-4-nitrobenzene carboximidoyl chloride and N-(4-methoxyphenyl) —4-methoxybenzene carboximidoyl chloride. These constitute one of the subjects of the invention.

The examples given below illustrate the invention without however limiting it.

Example 1 : 3-ethy1-4-(4-methoxyphenyl)-5-(U-nitrophenyl)-UH-1,2,4-triazole.

- Stage A : N-(4-methoxyphenyl)-4-nitrobenzene carboximidoyl chloride. 1.36 g of M-(4-methoxyphenyl)-4-nitrobenzamide (preparation given below) and 5 cm^ of thionyl chloride are heated to reflux for 6 hours, then 30 cm^ of benzene is added. The benzene and the thionyl chloride are eliminated under reduced pressure, ar.d the expected product is obtained, melting at 120° to 122° C.

Preoaration of the N-(4-methoxvDhenyl)-4-nitrobenzamide. 12-3 S of para-anisidine is added in small fractions to a suspension 3 containing 18.6 g of 4_nitrobenzoic acid chloride in 100 cm of pyridine and heated for 2 hours at reflux. After returning to ambient temper3 ature, the solution is poured into 500 cn of iced water and the precipitate formed is separated and washed with water, then dried under reduced pressure at 80° C, and 20 g of the expected product is formed, melting at 200° C.

Stage B : 2-(1-oxopropyl)hydrazide of N-(4-raethoxyphenyl)-4-nitro20 benzene carboximic acid. 2.8 cm^ of triethylamine i3 added to a solution containing 1.76 g 3 of propionic acid hydrazide (preparation given below) in 80 cm of toluene. 2.87 g of the product obtained at stage A is then added in one lot, with agitation for 15 minutes. After separating and drying, the residue obtained is taken up in 100 cm^ of water, then extracted with methylene chloride, dried and concentrated to dryness, and 2.2 g of the expected product is obtained, melting at 158° C.

Preparation of propionic acid hydrazide. 38.83 cm^ of hydrazine hydrate and 52.42 g of ethyl propionate 30 are taken to reflux for 18 hours. The expected product is obtained, = 100° C. 3-ethyl-4-(4-methoxypheny B-5-(4-nitrophenyl)-4H-1,2,4triazole. of the product obtained at stage 3 is taken to reflux for two hours in 60 cm^ of toluene. The toluene is evaporated, the residue is taken up with isopropyl oxide, and the solid obtained is recrystallized from a mixture of isopropyl oxide and isopropanol (2-1). The expected product is obtained, melting at 174°C. '· 6 mmHg Stage C : 4.38 g Example 2 : 3-ethyl-4-(4-methoxyphenvl)-5-(4-nitro-3-roethvlphenyl)-4H-1,2,4-triazole.

Stage A. : N-(4-methoxyphenyl-4-nitro-3-methylbenzene carboximidoyl chloride. g of N-(4-methoxyphenyl)-4-nitro-3-methyl benzamide (preparation given below) is heated for 20 hours at reflux in suspension in 70 cm of thionyl chloride.

The solvent is eliminated by entrainment with benzene, and after drying under reduced pressure at ambient temperature, 15 g of product is obtained melting towards 80°C.

Preparation of the N-(4-methoxypheny1)-4-nitro-3-methvlbenzamide.

The preparation is done as for the N-(4-methoxyphenyl)-4-nitrobenzamide (see stage A, example 1), starting with 15.5 g of 4-nitrometatoluyl chloride and 9.56 g of para-amisidine in the presence of pyridine. 16.7 g of the expected product is obtained.

Stage B. : 3-ethyl-4-(4-methoxyphenyl)-5-(4-nitro-3-methylphenyl)-4H-1,2,4-triazole. 1.4 cm of triethylamine, then 3 g of the product obtained at stage A are introduced into a solution containing 1.76 g of propionic acid hydrazide in 160 cm of toluene, this latter havng been brought to reflux and then cooled. After taking the whole for 1 hour to reflux, the toluene is eliminated under reduced pressure and the 3 3 residue is taken up by 50 cm of chloroform and 50 cm of water.

The aqueous phase is exracted with chloroform, the extracts are dried and concentrated, and an oil is obtained which is purified by chromatography on silica (eluting with ethyl acetate and cyclohexane (8-2)). 3 g of an oil is obtained which presents an Rf. of 0.6 on thin film chromatography (eluent : chloroform-methanol 9-1).

Example 3 N,N-dimethy1-4-[5-ethy1-4-(4-methoxyphenyl) —4H-1,2,4-triazol-3-yl]-2-methyl benzenamine. 2.6 g of the product obtained in example 4, 13 cm3 of formic aldehyde and 5.2 g of powdered zinc are cooled to 5° C, then 13 cm3 of pure acetic acid is slowly introduced. The temperature is allowed to return to the ambient, and after agitating for 20 hours and separating, 3 the zinc is washed with 25 cm of a mixture of acetic acid and water, 3 100 cm of methylene, 50 cm of water.

The filtrate is decanted, the aqueous phase is extracted with methylene chloride, the organic phase is washed with water, dried and concentrated. g of an oil is obtained which is taken up by 20 cm of isopropyl ether, then cooled to -50° C, returned to ambient temperature, separated and dried under reduced pressure at 60° C. .1.85 g of product is obtained which i3 re-crystallized twice in a mixture of ethyl acetate and isopropyl ether (4-6). 1.2 g of the expected product is obtained, melting at 131° C. - 13 Example 4 : 3-ethyl-4-(4-methoxvphenyl)-5-Γ4Γ(NN-dimethylamino)-phenyll-4H-l,2,4-triazole.

Under argon and with agitation, 1 kg of 4-dimethylamino-4-methoxy benzanilide (preparation given below), 8 litres of dichloromethane and 1130 cm^ of triethylamine are cooled to -40°C +. 1°C and, at this temperature, 2.6 litres of a solution of phosgene in toluene is introduced, with agitation, followed by re-heating to 20°C over 2 hours.

The solution so obtained is introduced into 40 litres of toluene previously heated to reflux, and at the same time a second solution containing 489 g of propionic acid hydrazide in 489 cm of dichloromethane is added, all the while keeping the temperature of the reacting medium at equal to or greater than 90°C.

Distillation is maintained during the introduction of the two solutions. At the end of the introduction, the volume so distilled off is about 30 litres, and the heating is stopped when the temperature of the reactional medium is equal to or greater that 100°C.

It is then cooled to 20°C and washed successively with water, with water containing sodium hydroxide (4-1) and again with water.

After extracting with dichloromethane, the extracts are dried, 100 g of active carbon is added, followed by agitation and separation, washing with dichloromethane and concentration by distilling under atmospheric pressure down to a volume of 2 litres. This is cooled to 20°C and kept for 16 hours under agitation, then separated, washed with toluene and dried at 60°C, so obtaining 984 g of crude product. 61.5 g of crude product is also recovered from the toluene mother liquors of crystallization.

Purification With agitation and under nitrogen, 1,045 g of the crude product is heated to reflux in 4,182 cm of toluene, then, over 15 minutes, 104.5 g of active carbon is added and agitation is kept up at reflux for 15 minutes, followed by separating while hot and washing with boiling toluene. After cooling to 20°C agitating for one night at 20°C, separating, washing with toluene and drying at 60°C, 862.6 g of the expected product is obtained, melting at 167°C.

Preparation of 4-dimethylamino-4-methoxybenzani1ide. 201 g of para-anisidine is added to a suspension of 300 g of 3 4-dimethylamino benzoic acid chloride in 1200 cm of pyridine and agitated until it is dissolved, then the whole is heated for 3 hours at reflux. After cooling to ambient temperature, the reactional medium is poured into 6 litres of iced water, the precipitate is separated and washed with water, then dried under reduced pressure and 423 g of the expected product is obtained, m.p. 173°C.

Example 1 : 5-r4-nitropheny11-4-(4-methoxyphenyl)methyl-4H-l,2,4-triazol-3-methanol (L form). cm of triethylamine is added at ambient temperature to a solution containing 2 equivalents of β-lactic acid hydrazide (preparation given below) in 60 cm of toluene. Then 4.3 g of N-(4-methoxyphenyl)-4-nitroenzene carboximidoyl chlorde (stage A of example 1) is added in two lots, with agitation for 4 hours at ambient temperature.

The whole is then taken to reflux for 4 hours in order to obtain cyclization, the toluene is eliminated under reduced pressure, and after washing with water, separating and drying, 4.34 g of crude product is obtained which is purified by chromatography under pressure (eluent : chloroform - ethyl acetate - methanol : 47 : 50 : 3), so obtaining 3 g of the expected product melting at 140°C.

Preparation of β-lactic acid hydrazide. 9.7 cm of ethyl lactate (L form) is introduced slowly at 50°C into 4.1 cm3 of hydrazine hydrate. After taking to reflux for 4 hours and evaporating under reduced pressure, a colourless oil is recovered which is utilised as it is for the preparation of the product of example 10.

Example 2 : 5-r4-(dimethylamino)-phenyll-4-(4-methoxyphenyl) g-methyl-4H-l,2,4-triazol-3-methanol (L form) The operation is done as indicated in example 5, starting with 3 g of the product of example 10, 6 g of powdered zinc, 15 cm of formic aldeyde and 15 cm of acetic acid. 1.12g of the expected product is obtained, melting at 145°C. - 15 Example 3 : 5-Γ4-(dimethylamino)pheny11-4-(4-methoxyphenyl)-ot-methyl-4H-1.2t4-triazol-3-methanol acetate (L form). 0.47 g of sodium hydride is added to a suspension containing 3.3 g of the product prepared in example 11 in 33 cm of tetrahydrofuran. This is agitated for 30 minutes, then 0.92 g of acetyl chloride is added, and the whole is kept under agitation for 16 hours under an inert atmosphere. After concentrating to dryness, the residue is taken up in 30 cm of water, agitated for 30 minutes, then the precipitate is separated, washed with water and dried. After purifying by chromatography under pressure (eluent : ethyl acetate - chloroform 8-2), 2.8 g of the expected product is obtained, which is re-crystallized from toluene, m.p. 208°C. [0D = -16° ± 1° (c = 1% chloroform) Analysis : ^21^24^4θ3 : 380.450 Calculated : C % 66.30 H % 6.36 N % 14.73 Found : 66.0 6.3 14.6 Example 4 : 5- Γ 4- (dimethyl ami nolphenyl 1-4- (4-methoxyphenyl) -α-methyl4H-1.2.4-triazol-3-methanol (DL form) 2.36 g of triethylamine is added to a suspension comprising 5 g of 4-dimethylamino-4-methoxy benzanilide (prepared as in example 12) in 50 cm^ of metylene chloride. This is cooled to -40°C, then over 20 - 16 cm3 of phosgene in toluene is added, and the whole is re-heaced to 20° C over 1 hour and 30 minutes. The solution so obtained is introduced into 200 cm3 of toluene heated to reflux, and simultaneously a solution containing 2.9 g of lactic acid hydrazide (DL form) in 6 cm of dimethylformamide is added. A part of the solvents is eliminated by distilling, then, after heating for 30 minutes to 107° - 110° C, the reactional medium is cooled and washed first with water, then with an N aqueous solution of sodium hydroxide and again with water. After extracting with methylene chloride and concentrating to dryness, 7.1 g of crude product is obtained which is re-crystallized from a mixture of ethyl acetylacetate and isopropyl ether (3-6), and then from pure ethyl acetate, m.p. 170° C.

Analysis : Calculated Found C19H22N4°2 Example 338.413 C % 67.43 H % 6.55 N % 16.55 67.2 6.8 16.3 Preparation of the lactic acid hydrazide (DL form). g of DL-methyl lactage and 24.2 g of hydrazide hydrate are heated for 4 hours 30 minutes at 100/110° C. The water is eliminated by entrainment with xylene and the expected product is obtained in the form of an oil which is used as it is for the preparation of the product of example 15.

-C 4-(dimethylamino) phenyl]-4-(4-me thoxypheny !)-;<-methyl-4H-1,2,4-triazol-3-methanol acetate -£DL form) Operating as in example 3, starting with 2.4 g of the product prepared in example 15, 0.336 g of sodium hydride and 0.660 g of acetyl chloride, 2.24 g of the expected product is obtained, which is re-crystallized from toluene, m.p. 190° C.

Analysis : C^H^N^O : 380.450 Calculated : C % 66.3 Η %'6.3& N % 14.73 Found : 66.4 6.5 14.8 Example 6 : Pharmaceutical compositions.

Tablets have been prepared answering to the following formula : Product of example 11 ............................ 50 mg Excipient q.s. for a tablet finishing at ......... 360 mg (Detail of excipient : lactose, talc, starch, magnesium stearate). - 17 Example 7 : Pharmacological study of the product of example 2 Analgesic activity.

The test employed is based on the fact pointed out by R.KOSTER et Coll., (Fed. Proc. 1959, 18 , 412) according to which the intraperitoneal injection of acetic acid causes, in mice, repeated movements of stretching and twisting which can continue for more than six hours. Analgesics prevent or diminish the syndrome, which can be considered as an external manifestation of a diffuse abdominal pain. A 1% solution of acetic acid in water is used. In these conditions, the dose releasing the syndrome is 0.01 cm / g, that is, 100 mg/kg of acetic acid.

The product under study is administered by oral route half an hour before the injection of the acetic acid, the mice having fasted since the day before the test.

The stretchings are observed and counted for each mouse during a 15 minute observation period beginning immediately after the injection of the acetic acid.

The results are expressed by means of the ϋΑ^θ, that is to say, the dose which enables a diminution of 50 % to be obtained in the number of stretchings by comparison with the control animals.

The θΑ^θ found was 4 mg/kg.

Anti-inflammatory activity : chronic arthritis with adjuvant (preventative treatment) In a rat, the injection of an adjuvant of Freund type in a hind paw causes the rapid appearance of a primary inflammatory lesion in this paw, then, after a latency period of 13 to 15 days, the appearance of a secondary arthritis affecting in particular the other hind paw. The test is carried out on male rats aged from 42 to 50 days, which receive as an intraplantary injection, 0.1 ml of *freund type adjuvant (suspension in vaseline oil of 6 mg per ml of killed mycobacterium butyricum).

The animals receive the product under study by oral route from day 0 (day of injection of the adjuvant) until the day before they are killed, which takes place on day 17. Control arthritic animals and normal control animals receive only the vehicle. The criteria by which the activity of the substances under study is appreciated are the increases in volume of the hind paws which are not injected (secondary inflammation) by comparison with the average volume of the corresponding paws of the normal controls.

The ΟΑ^θ is determined, that is to say, the dose which reduces 5 by 50 % the increases in volume of the hind paws of the treated animals by comparison with the control animals.

The result obtained has shown a notable activity of the product of example 11 in this test.

Claims (8)

1. Process for the preparation of compounds of formula (I a ): in which R 1 , R-, and R 4 , identical or different, in whatever position on the benzene nuclei, represent a hydrogen atom, an hydroxyl radical, an alkyl radical containing from 1 to 4 carbon atoms, an Oalk, radical, alk, representing an aikyl radical containing from 1 to 4 carbon atoms, an NH-, NHalk? radical, alk- rgpresenting an alkyl radical containing from I to 4 carbon atoms; a radical N alk-' ano < alk' -Ί t identical or different, reoresenting and alkyl raoica1 conta i n i ng from I to i caroon a toms, a halogen atom, a C? 3 radica1 or an NC 9 radica 1, or R, and R ? and/or R 3 and R 4 together form a methylenedioxy radical, R^ repr esents a -CHGH-alk., radica 1, or a O-CC-aik, radical, alk^ and alk-, identical or different, representing an alkyl radical containing from 1 to 4 carbon atoms, in their racemic or optically active forms, as well as their addition salts with acids wherein a compound of formula (Ii): in which Rp R 2 , R^ and R^ nave the significances already indicated, is submitted to the action of a chlorination agent so as to obtain an imidyl chloride of formula (III): which is submitted to the action of a hydrazide of formula (IV) H 2 N-NH-C0-Z in racemic or optically active form, in which Z is a -CH-alk, I I OH group, alk^ being an alkyl radical containing from I to 4 carbon atoms, so as to obtain a compound of formula (V), in racemic or optically active form: which is cyclized by heating so as to obtain a compound of formula (I), in racemic or optically active form, in which R is a -CH-alk 4 OH group, which if desired is esterified so as to obtain a product of formula (I) in which R^ is a -CH-alk 4 0-C0-alk 5 group, which products of formula (I) are submitted, if desired, to the action of an acid so as to form a salt.

2. Process according to claim 1, wherein at the start a compound of formula (II) is used in which one of the two substituents R^ or represents a hydrogen atom and the other substituent represents either a methoxy group in the para position, or an N0 2 or dimethylamino group in the para position and in which one of the two substituents Rg or R^ represents a hydrogen atom and the other substituent represents either a methoxy group in the para position, or an N0 2 or dimethylamino group in the para position and a hydrazide of formula (IV) in which Z represents a -CHOH-alk^ radical, alk^ representing an alkyl radical containing from 1 to 4 carbon atoms.

3. Compounds of formula (1^): in which Rp R 2 , Rg, R^ and R^ have the significances given in claim 1, in their racemic or optically active forms, as well as their addition salts with acids.

4. Compounds of formula (1^) as defined in claim 3 for which one of the two substituents R^ or R 2 represents a hydrogen atom, and - 22 the other substituent represents either a methoxy group in the para position, or a dimethylamino group in the para position and for which one of the substituents R^ or R^ represents a hydrogen atom, and the other substituent represents either a methoxy group in the para position, or a dimethylamino group in the para position, in their racemic or optically active forms, as well as their addition salts with acids.

5. 5-[4-(dimethylamino)phenyl]-(4-methoxypheny1)-4-methyl-4H-1,2, 4-triazole-3-methanol, in racemic or optically active form and its addition salts with acids.

6. As medicaments, the compounds of formula (1^), as defined in claims 3 and 4, as well as their addition salts with pharmaceutically acceptable acids.

7. A process for the preparation of compounds of the formula (I A ) as defined in Claim 1, substantially as hereinbefore described with reference to the examples.

8. Compounds of the formula (1^) as defined in Claim 1, whenever prepared by a process as claimed in any of claims 1, 2 or 7.